This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Genetic polymorphisms have been identified in drug-metabolizing enzyme genes of cytochrome-P450 (CYP) superfamily, such as CYP2D6, CYP2C9, and CYP2C19, which may help to explain significant differences in the metabolic rates for a variety of drugs. Such genetic polymorphisms have not been identified in CYP3A4 which is responsible for metabolizing more than 50% of prescription drugs. There is a critical need to elucidate the genetic polymorphisms that control variable gene expression and enzyme functions of this important protein. Gene expression of CYP3A4 is regulated at transcriptional level by a nuclear receptor mediated network, in which key transcriptional regulatory factors are nuclear receptors of pregnane-x-receptor (PXR), constitutive androstane receptor (CAR), and retinoid x receptor (RXR). Enzyme functions of CYP3A4 required a coenzyme, P450 oxidoreductase (POR), to provide electrons for oxidation reactions. The objective of this application is to determine the contribution of genetic polymorphisms in the PXR, CAR, RXRalpha, and POR genes to the manifestations of differential CYP3A4-mediated drug metabolic rates in liver. We propose to systematically exam functional influence of genetic polymorphisms in genes in the nuclear receptor mediated network on CYP3A4 gene expression and enzyme activity. The identification of genetic polymorphisms among these genes and to correlate these genetic polymorphisms with CYP3A4 enzyme activity, will provide a strong scientific foundation for further evaluation of inter-individual differences of drug metabolism for the 40% of prescription drugs metabolized by this enzyme.